Anat Cell Biol.  2024 Jun;57(2):163-171. 10.5115/acb.23.256.

The effect of biological mechanisms of melatonin on the proliferation of spermatogonial stem cells: a systematic review

• Navid S
• Saadatian Z
• Talebi A
• Toolee H
• Seyedi S

• KMID: 2556560
• DOI: http://doi.org/10.5115/acb.23.256

Abstract

In the last decade, melatonin has gained recognition as a potent scavenger and an effective antioxidant capable of neutralizing free radicals, including reactive oxygen species. Additionally, it exhibits anti-apoptotic properties. In this review, we will examine a compilation of articles that explore the cellular signaling function of melatonin on spermatogonial stem cells (SSCs) and adjacent cells such as Sertoli and Leydig cells. These cells play a crucial role in the proliferation of SSCs both in vitro and in vivo. In this review, we analyze the function of melatonin in the proliferation of SSCs from other aspects. For this purpose, we examine the articles based on the presence of melatonin on SSCs in four groups: As a supplement in SSCs medium culture, SSCs three-dimensional culture system, SSCs freezing medium, and as a therapeutic factor in vivo. Mechanisms of growth and proliferation of SSCs were considered. The purpose of this study is to investigate the potential effects of melatonin as a powerful antioxidant or growth stimulant for SSCs, both in vivo and in vitro.

Keyword

Melatonin; Spermatogonial stem cells; Proliferation

Figure

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  Fig. 1 Melatonin signaling pathways on spermatogonial stem cells and Sertoli cell. GDNF, glial cell line-derived neurotrophic factor; ERS, endoplasmic reticulum stress; PI3K, phosphatidylinositol 3-kinase; GSH, glutathione; ROS, reactive oxygen species [3, 35-35].

Reference

References

1. Hardeland R, Pandi-Perumal SR, Cardinali DP. 2006; Melatonin. Int J Biochem Cell Biol. 38:313–6. DOI: 10.1016/j.biocel.2005.08.020. PMID: 16219483.

2. Yang WC, Tang KQ, Fu CZ, Riaz H, Zhang Q, Zan LS. 2014; Melatonin regulates the development and function of bovine Sertoli cells via its receptors MT1 and MT2. Anim Reprod Sci. 147:10–6. DOI: 10.1016/j.anireprosci.2014.03.017. PMID: 24768045.

3. Sun TC, Li HY, Li XY, Yu K, Deng SL, Tian L. 2020; Protective effects of melatonin on male fertility preservation and reproductive system. Cryobiology. 95:1–8. DOI: 10.1016/j.cryobiol.2020.01.018. PMID: 32001217.

4. Heidarizadi S, Rashidi Z, Jalili C, Gholami M. 2022; Overview of biological effects of melatonin on testis: a review. Andrologia. 54:e14597. DOI: 10.1111/and.14597. PMID: 36168927.

5. Zhang S, Chen S, Li Y, Liu Y. 2017; Melatonin as a promising agent of regulating stem cell biology and its application in disease therapy. Pharmacol Res. 117:252–60. DOI: 10.1016/j.phrs.2016.12.035. PMID: 28042087.

6. Navid S, Rastegar T, Baazm M, Alizadeh R, Talebi A, Gholami K, Khosravi-Farsani S, Koruji M, Abbasi M. 2017; In vitro effects of melatonin on colonization of neonate mouse spermatogonial stem cells. Syst Biol Reprod Med. 63:370–81. DOI: 10.1080/19396368.2017.1358774. PMID: 28846448.

7. Li X, Chen X, Liu Y, Zhang P, Zheng Y, Zeng W. 2020; The histone methyltransferase SETDB1 modulates survival of spermatogonial stem/progenitor cells through NADPH oxidase. Front Genet. 11:997. DOI: 10.3389/fgene.2020.00997. PMID: 33133132. PMCID: PMC7567028.

8. Gholami M, Ahmadi SAY, Abaszadeh A, Khaki A. 2017; Protective effects of melatonin and ghrelin on spermatogenesis: a narrative review of the literature. Int J Reprod Biomed. 15:265–72. DOI: 10.29252/ijrm.15.5.265. PMID: 28744521. PMCID: PMC5510579.

9. Cruz MH, Leal CL, da Cruz JF, Tan DX, Reiter RJ. 2014; Role of melatonin on production and preservation of gametes and embryos: a brief review. Anim Reprod Sci. 145:150–60. DOI: 10.1016/j.anireprosci.2014.01.011. PMID: 24559971.

10. Marcantonini G, Bartolini D, Zatini L, Costa S, Passerini M, Rende M, Luca G, Basta G, Murdolo G, Calafiore R, Galli F. 2022; Natural cryoprotective and cytoprotective agents in cryopreservation: a focus on melatonin. Molecules. 27:3254. DOI: 10.3390/molecules27103254. PMID: 35630729. PMCID: PMC9145333.

11. Kozioł K, Broda D, Romerowicz-Misielak M, Nowak S, Koziorowski M. 2020; Melatonin concentration in peripheral blood and melatonin receptors (MT1 and MT2) in the testis and epididymis of male roe deer during active spermatogenesis. Theriogenology. 149:25–37. DOI: 10.1016/j.theriogenology.2020.03.025. PMID: 32234648.

12. Li C, Zhu X, Chen S, Chen L, Zhao Y, Jiang Y, Gao S, Wang F, Liu Z, Fan R, Sun L, Zhou X. 2017; Melatonin promotes the proliferation of GC-1 spg cells by inducing metallothionein-2 expression through ERK1/2 signaling pathway activation. Oncotarget. 8:65627–41. DOI: 10.18632/oncotarget.20019. PMID: 29029459. PMCID: PMC5630359.

13. Navid S, Abbasi M, Hoshino Y. 2017; The effects of melatonin on colonization of neonate spermatogonial mouse stem cells in a three-dimensional soft agar culture system. Stem Cell Res Ther. 8:233. DOI: 10.1186/s13287-017-0687-y. PMID: 29041987. PMCID: PMC5646105.

14. Kazemzadeh S, Rastegar T, Zangi BM, Malekzadeh M, Khanehzad M, Khanlari P, Madadi S, Bashghareh A, Hedayatpour A. 2021; Effect of a freezing medium containing melatonin on markers of pre-meiotic and post-meiotic spermatogonial stem cells (SSCs) after transplantation in an azoospermia mouse model due to testicular torsion. Reprod Sci. 28:1508–22. DOI: 10.1007/s43032-020-00447-5. PMID: 33481217.

15. Niu B, Li B, Wu C, Wu J, Yan Y, Shang R, Bai C, Li G, Hua J. 2016; Melatonin promotes goat spermatogonia stem cells (SSCs) proliferation by stimulating glial cell line-derived neurotrophic factor (GDNF) production in Sertoli cells. Oncotarget. 7:77532–42. DOI: 10.18632/oncotarget.12720. PMID: 27769051. PMCID: PMC5363602.

16. Deng SL, Chen SR, Wang ZP, Zhang Y, Tang JX, Li J, Wang XX, Cheng JM, Jin C, Li XY, Zhang BL, Yu K, Lian ZX, Liu GS, Liu YX. 2016; Melatonin promotes development of haploid germ cells from early developing spermatogenic cells of Suffolk sheep under in vitro condition. J Pineal Res. 60:435–47. DOI: 10.1111/jpi.12327. PMID: 26993286.

17. Reda A, Albalushi H, Montalvo SC, Nurmio M, Sahin Z, Hou M, Geijsen N, Toppari J, Söder O, Stukenborg JB. 2017; Knock-out serum replacement and melatonin effects on germ cell differentiation in murine testicular explant cultures. Ann Biomed Eng. 45:1783–94. DOI: 10.1007/s10439-017-1847-z. PMID: 28488216. PMCID: PMC5489632.

18. Zhang T, Zhou Y, Li L, Zhao Y, De Felici M, Reiter RJ, Shen W. 2018; Melatonin protects prepuberal testis from deleterious effects of bisphenol A or diethylhexyl phthalate by preserving H3K9 methylation. J Pineal Res. 65:e12497. DOI: 10.1111/jpi.12497. PMID: 29655234.

19. Deng SL, Wang ZP, Jin C, Kang XL, Batool A, Zhang Y, Li XY, Wang XX, Chen SR, Chang CS, Cheng CY, Lian ZX, Liu YX. 2018; Melatonin promotes sheep Leydig cell testosterone secretion in a co-culture with Sertoli cells. Theriogenology. 106:170–7. DOI: 10.1016/j.theriogenology.2017.10.025. PMID: 29073541.

20. Xu D, Liu L, Zhao Y, Yang L, Cheng J, Hua R, Zhang Z, Li Q. 2020; Melatonin protects mouse testes from palmitic acid-induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1-dependent manner. J Pineal Res. 69:e12690. DOI: 10.1111/jpi.12690. PMID: 32761924.

21. Lv Y, Li T, Yang M, Su L, Zhu Z, Zhao S, Zeng W, Zheng Y. 2021; Melatonin attenuates chromium (VI)-induced spermatogonial stem cell/progenitor mitophagy by restoration of METTL3-mediated RNA N6-methyladenosine modification. Front Cell Dev Biol. 9:684398. DOI: 10.3389/fcell.2021.684398. PMID: 34150779. PMCID: PMC8212693.

22. Lv Y, Zhang P, Guo J, Zhu Z, Li X, Xu D, Zeng W. 2018; Melatonin protects mouse spermatogonial stem cells against hexavalent chromium-induced apoptosis and epigenetic histone modification. Toxicol Appl Pharmacol. 340:30–8. DOI: 10.1016/j.taap.2017.12.017. PMID: 29289671.

23. Alinezhad G, Eslampour MA, Movahedin M, Khorrami N, Tajik P. 2023; Impact of melatonin on the colonies diameter, apoptosis status and apoptosis related genes expression in sheep's spermatogonial stem cells. Vet Res Biol Prod. 36:34–40.

24. Gholami M, Saki G, Hemadi M, Khodadadi A, Mohammadi-Asl J. 2014; Melatonin improves spermatogonial stem cells transplantation efficiency in azoospermic mice. Iran J Basic Med Sci. 17:93–9. PMID: 24711891. PMCID: PMC3976745.

25. Gholami M, Saki G, Hemadi M, Khodadadi A, Mohammadiasl J. 2015; Melatonin effect on immature mouse testicular tissues, vitrified-thawed with different cryoprotectant media. Jentashapir J Health Res. 6:e28704. DOI: 10.5812/jjhr.28704v2.

26. Saki G, Mirhoseini M, Hemadi M, Khodadadi A, Beygom Talebpour Amiri F. 2016; The effect of the melatonin on cryopreserved mouse testicular cells. Int J Reprod Biomed. 14:23–8. DOI: 10.29252/ijrm.14.1.23. PMID: 27141545. PMCID: PMC4837917.

27. Feng TY, Li Q, Ren F, Xi HM, Lv DL, Li Y, Hu JH. 2020; Melatonin protects goat spermatogonial stem cells against oxidative damage during cryopreservation by improving antioxidant capacity and inhibiting mitochondrial apoptosis pathway. Oxid Med Cell Longev. 2020:5954635. DOI: 10.1155/2020/5954635. PMID: 33488926. PMCID: PMC7790556.

28. Kazemzadeh S, Mohammadpour S, Madadi S, Babakhani A, Shabani M, Khanehzad M. 2022; Melatonin in cryopreservation media improves transplantation efficiency of frozen-thawed spermatogonial stem cells into testes of azoospermic mice. Stem Cell Res Ther. 13:346. DOI: 10.1186/s13287-022-03029-1. PMID: 35883101. PMCID: PMC9327150.

29. Nazeri T, Hedayatpour A, Kazemzadeh S, Safari M, Safi S, Khanehzad M. 2022; Antioxidant effect of melatonin on proliferation, apoptosis, and oxidative stress variables in frozen-thawed neonatal mice spermatogonial stem cells. Biopreserv Biobank. 20:374–83. DOI: 10.1089/bio.2021.0128. PMID: 35984941.

30. Hemadi M, Shokri S, Moramezi F, Nikbakht R, Sobhani A. 2014; Potential use of melatonin supplementation to protect vitrified testicular grafts from hypoxic-ischaemic damage. Andrologia. 46:513–21. DOI: 10.1111/and.12110. PMID: 23701511.

31. Abd El Aziz DH, Metwally HG. 2013; The effect of stem cell therapy versus melatonin on the changes induced by busulfan in the testes of adult rat: histological and immunohistochemical studies. Egypt J Histol. 36:175–84. DOI: 10.1097/01.EHX.0000425579.77855.ea.

32. Cui Y, Ren L, Li B, Fang J, Zhai Y, He X, Du E, Miao Y, Hua J, Peng S. 2017; Melatonin relieves busulfan-induced spermatogonial stem cell apoptosis of mouse testis by inhibiting endoplasmic reticulum stress. Cell Physiol Biochem. 44:2407–21. DOI: 10.1159/000486165. PMID: 29268276.

33. Deng SL, Zhang Y, Yu K, Wang XX, Chen SR, Han DP, Cheng CY, Lian ZX, Liu YX. 2017; Melatonin up-regulates the expression of the GATA-4 transcription factor and increases testosterone secretion from Leydig cells through RORα signaling in an in vitro goat spermatogonial stem cell differentiation culture system. Oncotarget. 8:110592–605. DOI: 10.18632/oncotarget.22855. PMID: 29299171. PMCID: PMC5746406.

34. Li B, He X, Zhuang M, Niu B, Wu C, Mu H, Tang F, Cui Y, Liu W, Zhao B, Peng S, Li G, Hua J. 2018; Melatonin ameliorates busulfan-induced spermatogonial stem cell oxidative apoptosis in mouse testes. Antioxid Redox Signal. 28:385–400. DOI: 10.1089/ars.2016.6792. PMID: 28027652.

35. Du Z, Xu S, Hu S, Yang H, Zhou Z, Sidhu K, Miao Y, Liu Z, Shen W, Reiter RJ, Hua J, Peng S. 2018; Melatonin attenuates detrimental effects of diabetes on the niche of mouse spermatogonial stem cells by maintaining Leydig cells. Cell Death Dis. 9:968. DOI: 10.1038/s41419-018-0956-4. PMID: 30237484. PMCID: PMC6148071.

36. Zhang X, Xia Q, Wei R, Song H, Mi J, Lin Z, Yang Y, Sun Z, Zou K. 2019; Melatonin protects spermatogonia from the stress of chemotherapy and oxidation via eliminating reactive oxidative species. Free Radic Biol Med. 137:74–86. DOI: 10.1016/j.freeradbiomed.2019.04.009. PMID: 30986493.

37. Yang D, Wei Y, Lu Q, Qin D, Zhang M, Du X, Xu W, Yu X, He C, Li N, Peng S, Li G, Hua J. 2021; Melatonin alleviates LPS-induced endoplasmic reticulum stress and inflammation in spermatogonial stem cells. J Cell Physiol. 236:3536–51. DOI: 10.1002/jcp.30088. PMID: 32996162.

38. Li T, Zheng Y, Li T, Guo M, Wu X, Liu R, Liu Q, You X, Zeng W, Lv Y. 2022; Potential dual protective effects of melatonin on spermatogonia against hexavalent chromium. Reprod Toxicol. 111:92–105. DOI: 10.1016/j.reprotox.2022.05.009. PMID: 35643323.